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PreprintCited by 4Muscle Physiology and DisordersGenomics and Rare DiseasesCardiomyopathy and Myosin Studies

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Profiling of pathogenic variants in Japanese patients with sarcoglycanopathy

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Shimazaki, Rui, Saito, Yoshihiko, Awaya, Tomonari, Minami, Narihiro, Kurosawa, Ryo, Hosokawa, Motoyasu, Ohara, Hiroaki, Hayashi, Shinichiro, Takeuchi, Akihide, Hagiwara, Masatoshi, Hayashi, Yukiko K, Noguchi, Satoru, Nishino, Ichizo·2024·Orphanet Journal of Rare Diseases
DOI 10.21203/rs.3.rs-4146610/v1PMC PMC11699685

Preprint — published as 10.1186/s13023-024-03521-2 · Paper page

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Abstract

Background Sarcoglycanopathies (SGPs) are limb-girdle muscular dystrophies (LGMDs) that can be classified into four types, LGMDR3, LGMDR4, LGMDR5, and LGMDR6, caused by mutations in the genes, SGCA, SGCB, SGCG, and SGCD, respectively. SGPs are relatively rare in Japan. This study aims to profile the genetic variants that cause SGPs in Japanese patients. Methods Clinical course and pathological findings were retrospectively reviewed in Japanese patients with SGP. Genetic analyses were performed using a combination of targeted resequencing with a hereditary muscle disease panel, whole genome sequencing, multiplex ligation-dependent probe amplification, and long-read sequencing. The structures of transcripts with aberrant splicing were also determined by RT-PCR, RNA-seq, and in silico prediction. Results We identified biallelic variants in SGC genes in 53 families, including three families with LGMDR6, which had not been identified in Japan so far. SGCA was the most common causative gene, accounting for 56% of cases, followed by SGCG, SGCB, and SGCD, at 17%, 21%, and 6%, respectively. Missense variants in SGCA were very frequent at 78.3%, while they were relatively rare in SGCB, SGCG, and SGCD at 11.1%, 18.2%, and 16.6%, respectively. We also analyzed the haplotypes of alleles carrying three variants found in multiple cases: c.229C > T in SGCA, c.325C > T in SGCB, and exon 6 deletion in SGCG; two distinct haplotypes were found for c.229C > T in SGCA, while each of the latter two variants was on single haplotypes. Conclusions We present genetic profiles of Japanese patients with SGPs. Haplotype analysis indicated common ancestors of frequent variants. Our findings will support genetic diagnosis and gene therapy.

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Metadata

Authors
Shimazaki, R., Saito, Y., Awaya, T., Minami, N., Kurosawa, R., Hosokawa, M., Ohara, H., Hayashi, S., Takeuchi, A., Hagiwara, M., Hayashi, Y. K., Noguchi, S., & Nishino, I.
Affiliations
  • National Center of Neurology and Psychiatry (JP)
  • Kyoto University (JP)
  • Ehime University (JP)
  • Tokyo Medical University (JP)
Corresponding author
Noguchi, Satoru
ORCID
Venue
Orphanet Journal of Rare Diseases
Publisher
Springer Science and Business Media LLC
Published
2024-12-18
Volume
20
Issue
1
Pages
1-1
ISSN
1750-1172 (ISSN-L)
DOI
10.21203/rs.3.rs-4146610/v1
PMC
PMC11699685
OpenAlex
W4406052185
Cited by
4
References
1
Citations by year
2026: 2 · 2025: 2
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Orphanet Journal of Rare Diseases (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Japan Agency for Medical Research and Development (JP23ak0101195s0101, JP23ek0109617s0402, JP20ek0109490h0001)
  • National Center of Neurology and Psychiatry
  • Japan Society for the Promotion of Science (22KJ2023, 23K24059, 23K16771)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
Keywords
sarcoglycanopathies, limb-girdle muscular dystrophy, SGCA, SGCD, pathogenic variants, haplotype analysis, missense mutations, exon deletion, Japanese patients, genetic diagnosis, gene therapy
MeSH terms
East Asian People, Adolescent, Adult, Child, Child, Preschool, Female, Humans, Japan, Male, Middle Aged, Mutation, Retrospective Studies, Sarcoglycans, Young Adult, Sarcoglycanopathies

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